Per- and polyfluoroalkyl substances and human health outcomes: An umbrella review of systematic reviews with meta-analyses of observational studies.

BACKGROUND: Although evidence on the association between per- and polyfluoroalkyl substances (PFASs) and human health outcomes has grown exponentially, specific health outcomes and their potential associations with PFASs have not been conclusively evaluated. METHODS: We conducted a comprehensive search through the databases of PubMed, Embase, and Web of Science from inception to February 29, 2024, to identify systematic reviews with meta-analyses of observational studies examining the associations between the PFASs and multiple health outcomes. The quality of included studies was evaluated using the A Measurement Tool to Assess Systematic Reviews (AMSTAR) tool, and credibility of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) criteria. The protocol of this umbrella review (UR) had been registered in PROSPERO (CRD 42023480817). RESULTS: The UR identified 157 meta-analyses from 29 articles. Using the AMSTAR measurement tool, all articles were categorized as of moderate-to-high quality. Based on the GRADE assessment, significant associations between specific types of PFASs and low birth weight, tetanus vaccine response, and triglyceride levels showed high certainty of evidence. Moreover, moderate certainty of evidence with statistical significance was observed between PFASs and health outcomes including lower BMI z-score in infancy, poor sperm progressive motility, and decreased risk of preterm birth as well as preeclampsia. Fifty-two (33%) associations (e.g., PFASs and gestational hypertension, cardiovascular disease, etc) presented low certainty evidence. Additionally, eighty-five (55%) associations (e.g., PFASs with infertility, lipid metabolism, etc) presented very low certainty evidence. CONCLUSION: High certainty of evidence supported that certain PFASs were associated with the incidence of low birth weight, low efficiency of the tetanus vaccine, and low triglyceride levels.

Expedient and divergent synthesis of unnatural peptides through cobalt-catalyzed diastereoselective umpolung hydrogenation.

The development of a reliable method for asymmetric synthesis of unnatural peptides is highly desirable and particularly challenging. In this study, we present a versatile and efficient approach that uses cobalt-catalyzed diastereoselective umpolung hydrogenation to access noncanonical aryl alanine peptides. This protocol demonstrates good tolerance toward various functional groups, amino acid sequences, and peptide lengths. Moreover, the versatility of this reaction is illustrated by its successful application in the late-stage functionalization and formal synthesis of various representative chiral natural products and pharmaceutical scaffolds. This strategy eliminates the need for synthesizing chiral noncanonical aryl alanines before peptide formation, and the hydrogenation reaction does not result in racemization or epimerization. The underlying mechanism was extensively explored through deuterium labeling, control experiments, HRMS identification, and UV-Vis spectroscopy, which supported a reasonable CoI/CoIII catalytic cycle. Notably, acetic acid and methanol serve as safe and cost-effective hydrogen sources, while indium powder acts as the terminal electron source.

Cobalt-Catalyzed Asymmetric Deuteration of α-Amidoacrylates for Stereoselective Synthesis of α,ß-Dideuterated α-Amino Acids.

A cobalt-catalyzed deuteration of amidoacrylates using deuterated methanol afforded α,ß-dideuterio-α-amino esters in excellent enantiomeric ratios (mostly >95 : 5) and almost complete deuteration (99 %). The new protocol was used to prepare dideuterio-α-amino acid fragments in some drugs. Furthermore, the stereoselective deuteration was applied in a concise synthesis of dideuterio l-DOPA.

Argon mitigates post-stroke neuroinflammation by regulating M1/M2 polarization and inhibiting NF-κB/NLRP3 inflammasome signaling.

Neuroinflammation plays a vital role in cerebral ischemic stroke (IS). In the acute phase of IS, microglia are activated toward the pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes. Argon, an inert gas, can reduce neuroinflammation and alleviate ischemia/reperfusion (I/R) injury. However, whether argon regulates M1/M2 polarization to protect against I/R injury as well as the underlying mechanism has not been reported. In this study, we analyzed the activation and polarization of microglia after I/R injury with or without argon administration and explored the effects of argon on NLRP3 inflammasome-mediated inflammation in microglia in vitro and in vivo. The results showed that argon application inhibited the activation of M1 microglia/macrophage in the ischemic penumbra and the expression of proteins related to NLRP3 inflammasome and pyroptosis in microglia. Argon administration also inhibited the expression and processing of IL-1ß, a primary pro-inflammatory cytokine. Thus, argon alleviates I/R injury by inhibiting pro-inflammatory reactions via suppressing microglial polarization toward M1 phenotype and inhibiting the NF-κB/NLRP3 inflammasome signaling pathway. More importantly, we showed that argon worked better than the specific NLRP3 inflammasome inhibitor MCC950 in suppressing neuroinflammation and protecting against cerebral I/R injury, suggesting the therapeutic potential of argon in neuroinflammation-related neurodegeneration diseases as a potent gas inhibitor of the NLRP3 inflammasome signaling pathway.

Imaging of hypochlorous acid in mitochondria using an asymmetric near-infrared fluorescent probe with large Stokes shift.

Small-molecule near-infrared (NIR) imaging facilitates deep tissue penetration, low autofluorescence, non-invasive visualization, and a relatively simple operation. As such it has emerged as a popular technique for tracking biological species and events. However, the small Stokes shift of most NIR dyes often results in a low signal-to-noise ratio and self-quenching due to crosstalk between the excitation and emission spectra. With this research, we developed a NIR-based fluorescent probe WD-HOCl for hypochlorous acid (HOCl) detection using the NIR dye TJ730 as the fluorophore, which exhibits a large Stokes shift of 156 nm, with no crosstalk between the excitation and emission spectra. It contains acyl hydrazide as the responsive group and a pyridinium cation as the mitochondria-targeting group. The fluorescence intensity of WD-HOCl was enhanced by 30.1-fold after reacting with HOCl. Imaging studies performed using BV-2 cells indicated that WD-HOCl could be used for endogenous HOCl detection and imaging in living cells exposed to glucose and oxygen deprivation/reperfusion. Finally, we demonstrated that inhibiting the expression of NOX2 reduced the HOCl levels and the severity of oxidative stress during stroke in a mouse model.

Advanced aqueous sodium-ion capacitors based on Ni0.25Mn0.75O nanoparticles encapsulated in electrospinning carbon nanofibers.

Manganese oxides are promising cathode material candidates with appropriate positive potential windows for low-cost and safe aqueous sodium-ion capacitors (ASICs). However, their low electrical conductivity issue and the lack of advanced binder-free manganese oxide-based electrodes severely restrict their practical capacitance and application in flexible ASICs. Here, Ni0.25Mn0.75O (NMO) nanoparticles uniformly encapsulated in carbon nanofiber films with excellent flexibility are fabricated by electrospinning and subsequent carbonization. The uniformly amorphous carbon layer enhances the conductivity, avoids dissolution and alleviates the volume or stress change of NMO during ion intercalation or mechanical deformation. More importantly, compared with the flexible electrodes prepared by traditional methods, electrospinning materials can be directly used as binder-free electrodes, which can effectively simplify the process and improve the energy density. Finally, a 2.4 V flexible quasi-solid-state ASIC device is integrated, which exhibits a high energy density of 5.95 mWh cm-3, a high power density of 670 mW cm-3 and an outstanding stability of 1000 cycles. This work offers an effective materials engineering strategy for high-performance binder-free NMO-based cathodes and advanced flexible ASICs.

Evaluation of Feature Selection for Alzheimer's Disease Diagnosis.

Accurate recognition of patients with Alzheimer's disease (AD) or mild cognitive impairment (MCI) is important for the subsequent treatment and rehabilitation. Recently, with the fast development of artificial intelligence (AI), AI-assisted diagnosis has been widely used. Feature selection as a key component is very important in AI-assisted diagnosis. So far, many feature selection methods have been developed. However, few studies consider the stability of a feature selection method. Therefore, in this study, we introduce a frequency-based criterion to evaluate the stability of feature selection and design a pipeline to select feature selection methods considering both stability and discriminability. There are two main contributions of this study: (1) It designs a bootstrap sampling-based workflow to simulate real-world scenario of feature selection. (2) It develops a decision graph to determine the optimal combination of supervised and unsupervised feature selection both considering feature stability and discriminability. Experimental results on the ADNI dataset have demonstrated the feasibility of our method.

Development of a ratiometric nitric oxide probe with baseline resolved emissions by an ESIPT and rhodol ring opened-closed integrated two-photon platform.

In recent years, reflecting the degree of cellular inflammation through in situ monitoring of nitric oxide using fluorescence sensing has received much attention due to many merits such as non-invasiveness and easy operation. In particular, two-photon excitation microscopy can significantly improve the imaging resolution and visualization time. In the meantime, a ratiometric-based nitric oxide fluorescent sensor can avoid the interference of many factors, including light source intensity, solvent scattering degree, solvent color, solvent viscosity, probe distribution, and instrument performance, and improve the accuracy of the result. However, the mutual interference of two emission peaks is still an issue restricting the development of this field. In this work, the Rh-NO-F dye obtained by modifying the rhodol dye with benzothiazole exhibited excited state intramolecular proton transfer (ESIPT) in the closed ring state. In the open ring state, however, the emission wavelength can be significantly red-shifted by increasing the degree of dye conjugation. By introducing o-phenylenediamine, the recognition domain of NO, we successfully designed and synthesized a ratiometric two-photon NO fluorescent probe, Rh-NO-P, which showed a 154 nm increase in the maximum emission wavelength before and after the response and almost no interference between the two emission peaks. Confocal imaging showed that the probe could achieve in situ detection of exogenous NO fluctuations in cells. The probe was also successfully applied to detect the changes in NO content during wound healing in mice.

Body Weight-Supported Treadmill Training Ameliorates Motoneuronal Hyperexcitability by Increasing GAD-65/67 and KCC2 Expression via TrkB Signaling in Rats with Incomplete Spinal Cord Injury.

Spasticity is a typical consequence after spinal cord injury (SCI). The critical reasons are reducing the synthesis of Gamma-Aminobutyric Acid (GABA), glycine and potassium chloride co-transporter 2 (KCC2) inside the distal spinal cord. The current work aimed to test whether exercise training could increase the expression of glutamic acid decarboxylase 65/67 (GAD-65/67, the key enzymes in GABA synthesis) and KCC2 in the distal spinal cord via tropomyosin-related kinase B (TrkB) signaling. The experimental rats were randomly assigned to the following five groups: Sham, SCI/phosphate-buffered saline (PBS), SCI-treadmill training (TT)/PBS, SCI/TrkB-IgG, and SCI-TT/TrkB-IgG. After that, the model of T10 contusion SCI was used, then TrkB-IgG was used to prevent TrkB activity at 7 days post-SCI. Body weight-supported treadmill training started on the 8th day post-SCI for four weeks. The Hmax/Mmax ratio and the rate-dependent depression of H-reflex were used to assess the excitability of spinal motoneuronal networks. Western blotting and Immunohistochemistry techniques were utilized for measuring the expression of GAD-65, GAD-67, and KCC2. The findings revealed that exercise training could reduce motoneuronal excitability and boost GAD-65, GAD-67, and KCC2 production in the distal region of the spinal cord after SCI. The effects of exercise training were decreased after the TrkB signaling was inhibited. The present exploration demonstrated that exercise training increases GAD-65, GAD-67, and KCC2 expression in the spinal cord via TrkB signaling and that this method could also improve rats with motoneuronal hyperexcitability and spasticity induced by incomplete SCI.

Interpretable Recognition for Dementia Using Brain Images.

Machine learning-based models are widely used for neuroimage-based dementia recognition and achieve great success. However, most models omit the interpretability that is a very important factor regarding the confidence of a model. Takagi-Sugeno-Kang (TSK) fuzzy classifiers as the high interpretability and promising classification performance have widely used in many scenarios. TSK fuzzy classifier can generate interpretable fuzzy rules showing the reasoning process. However, when facing high-dimensional data, the antecedent become complex which may reduce the interpretability. In this study, to keep the antecedent of fuzzy rule concise, we introduce the subspace clustering technique and use it for antecedent learning. Experimental results show that the used model can generate promising recognition performance as well as concise fuzzy rules.

Highly Sensitive Near-Infrared Imaging of Peroxynitrite Fluxes in Inflammation Progress.

Inflammation is an important protection reaction in living organisms associated with many diseases. Since peroxynitrite (ONOO-) is engaged in the inflammatory processes, illustrating the key nexus between ONOO- and inflammation is significant. Due to the lack of sensitive ONOO- in vivo detection methods, the research still remains at its infancy. Herein, a highly sensitive NIR fluorescence probe DDAO-PN for in vivo detection of ONOO- in inflammation progress was reported. The probe responded to ONOO- with significant NIR fluorescence enhancement at 657 nm (84-fold) within 30 s in solution. Intracellular imaging of exogenous ONOO- with the probe demonstrated a 68-fold fluorescence increase (F/F0). Impressively, the probe can in vivo detect ONOO- fluxes in LPS-induced rear leg inflammation with a 4.0-fold fluorescence increase and LPS-induced peritonitis with an 8.0-fold fluorescence increase The remarkable fluorescence enhancement and quick response enabled real-time tracking of in vivo ONOO- with a large signal-to-noise (S/N) ratio. These results clearly denoted that DDAO-PN was able to be a NIR fluorescence probe for in vivo detection and high-fidelity imaging of ONOO- with high sensitivity and will boost the research of inflammation-related diseases.

Effect of melatonin on regeneration of cortical neurons in rats with traumatic brain injury.

PURPOSE: To investigate the effect of melatonin on regeneration of cortical neurons in rats with traumatic brain injury (TBI). METHODS: Sprague-Dawley rats (n=36) were randomly divided into sham, TBI+vehicle and TBI+melatonin groups. Cerebral blood flow and cognitive function were observed via laser Doppler flowmetry and by Morris water maze testing, respectively. The serum malondialdehyde (MDA) and superoxide dismutase (SOD) levels were used to assess oxidative stress. Immunofluorescence and terminal deoxynucleotidyl transferase dUTP nick end labelling assay was used to observe the newborn neurons and apoptotic cells. RESULTS: Cerebral blood flow in the TBI+melatonin group was higher than that of the TBI+vehicle group at one, 12, 24 and 48 h post-injury, but the difference was not statistically significant (P>0.05). The cognitive function of the rats was better in the TBI+melatonin group than the TBI+vehicle group (P.

Activatable Two-Photon Near-Infrared Fluorescent Probe Tailored toward Peroxynitrite In Vivo Imaging in Tumors.

A malignant tumor remains one of the leading causes of deaths across the world. Thus, diagnosis of tumor development with noninvasive visualizing methods is significant for tumor therapy. Herein, an activatable two-photon NIR fluorescent probe DHQ-Rd-PN for in vivo imaging of peroxynitrite in a tumor was elaborately designed. The probe demonstrated an increased NIR emission in response to peroxynitrite in vitro, which ensured that the probe detects ONOO- in cell and in vivo. Cellular imaging results disclosed that the probe was competent to detect adscititious ONOO- level change in HeLa cells, as well as endogenous ONOO- concentration in lipopolysaccharides (LPS) and IFN-γ-stimulated RAW 264.7 cells. Additionally, zebrafish in vivo imaging revealed that the probe accumulated in the pancreas and was lightened up by the addition of ONOO-. Remarkably, the probe can be harnessed to image an ONOO- production profile in xenograft 4T1 tumor mice by both one-photon and two-photon in vivo fluorescence imaging. Benefiting with the two-photon excitable properties and NIR emissive properties, the probe can be used for noninvasive in vivo imaging of ONOO- in the onset and development of tumors for the first time. This work provided a noninvasive and efficient detection method for ONOO- in a tumor, which would find more applications in tumor diagnosis and therapies.

A highly specific probe for the imaging of inflammation-induced endogenous nitric oxide produced during the stroke process.

In this study, a turn-on two-photon fluorescent probe (Lyso-TP-NO) for nitric oxide (NO) was developed. It was synthesized using 4-ethylamino-1,8-naphthalimide as the two-photon fluorophore and N-methylaniline moiety as the reaction site. The probe and fluorophore were tested under one- and two-photon modes. The fluorescence intensity of the system was enhanced 23.1-fold after reacting with NO in the one-photon mode. However, the maximal two-photon action cross-section value of 200 GM was obtained under excitation at 840 nm. The probe exhibits high selectivity and sensitivity over other reactive oxygen species (ROS) and reactive nitrogen species (RNS), with a detection limit as low as 3.3 nM. The two-photon fluorescence imaging of living cells and mouse brain tissues can capture inflammation-induced endogenous NO production in lysosomes during stroke occurrence.

A highly specific and ultrasensitive probe for the imaging of inflammation-induced endogenous hypochlorous acid.

A turn-on two-photon fluorescent probe HCA-Green for hypochlorous acid (HOCl) was synthesized using 4-methylamino-1,8-naphthalimide (MNA) as a two-photon fluorophore and p-hydroxyaniline as a leaving-recognition domain. Both the probe and the fluorophore were investigated under one- and two-photon excitation modes. The fluorescence intensity of the probe was enhanced by ∼229-fold and ∼193-fold under one-photon and two-photon excitation, respectively, after reacting with HOCl. A maximal two-photon action cross-section of 50 GM was obtained under excitation at 810 nm. The probe exhibited high sensitivity with a detection limit of 42.3 nM, as well as high selectivity, low cytotoxicity, and good photostability. Two-photon microscopy (TPM) was conducted to visualize HOCl levels in living cells and tissues. The production of endogenous HOCl induced by lipopolysaccharide-mediated inflammation was successfully monitored with this probe.

Simultaneous voltammetric determination of acetaminophen and dopamine using a glassy carbon electrode modified with copper porphyrin-exfoliated graphene.

Graphene nanosheets (GSs) were prepared via liquid-phase non-covalent exfoliation of graphite powder in N,N-dimethylformamide under the assistance of copper(II) meso-tetra(4-carboxyphenyl)porphyrin tetrasodium salt Na4(CuTCPP). A glassy carbon electrode (GCE) was modified with a film of such GSs which, due to the good electrical conductivity of graphene and the electrocatalytic properties of Na4(CuTCPP), is capable of simultaneous determination of acetaminophen (AC) and dopamine (DA). The peak currents, best measured at voltage of 0.2 V (for DA) and 0.4 V (for AC; both vs. SCE), increase linearly in the 0.0024-3.6 µM and 0.004-7.6 µM concentration ranges, respectively. The detection limits are 0.8 nM for DA and 0.7 nM for AC. The sensor was successfully applied to the simultaneous determination of AC and DA in pharmaceutical preparations and spiked human serum. The results were in good agreement with those obtained for the same samples by HPLC. Graphical abstract Graphene nanosheets were prepared via a facile liquid-phase exfoliation of graphite with the assistance of copper(II) meso-tetra(4-carboxyphenyl)porphyrin tetrasodium salt. A graphene nanosheet-film modified glassy carbon electrode was fabricated to determine acetaminophen and dopamine through a simple and effective strategy.

[Protective effects of LBP on cerebral ischemia reperfusion injury in mice and mechanism of inhibiting NF-κB, TNF-α, IL-6 and IL-1ß].

To observe the protective effects of Lycium barbarum polysaccharides (LBP) on cerebral ischemia reperfusion injury in mice and explore its mechanism. Common carotid artery thread was used to cause middle cerebral artery ischemia, and the thread was taken out after 2 h ischemia to achieve cerebral ischemia reperfusion injury in mice. Therefore, the transient middle cerebral artery occlusion (tMCAO) models were established to observe the effects of LBP (25,50, 100 mg•kg⁻¹) on neurological outcome, infarct size and water contents. HE staining was used to observe its effects on neurocytes of cerebral tissues in mice. Western blotting was used to evaluate the protein expression levels of NF-κB p65. ELISA was used to evaluate the levels of TNF-α, IL-6 and IL-1ß in the serum. According to the results, LBP markedly improved neurologic deficits, and decreased infarct size and water contents at 24 h after reperfusion in mice. Pathological section of brain tissues also proved its protective effects on neurocytes. Western blot analysis indicated that LBP markedly down-regulated the protein level of NF-κB p65. ELISA indicated that LBP decreased the levels of TNF-α, IL-6 and IL-1ß in the serum 24 h after reperfusion.In conclusion, LBP has protective effects on cerebral ischemia reperfusion injury in mice, and this effect may be associated with inhibiting NF-κB and inflammatory reactions.

Development of a Silicon-Rhodamine Based Near-Infrared Emissive Two-Photon Fluorescent Probe for Nitric Oxide.

Two-photon (TP) fluorescent probes are potential candidates for near-infrared (NIR) imaging which holds great promise in biological research. However, currently, most TP probes emit at wavelength <600 nm, which impedes their practical applications. In this work, we explored the TP properties of a silicon-rhodamine (SiR) derivative and hence developed the first SiR scaffold based "NIR-to-NIR" TP probe (SiRNO) for nitric oxide (NO). SiRNO exhibited high sensitivity and specificity, as well as fast response for NO detection. It was able to track the subtle variation of intracellular NO content in live cells. Owing to the NIR excitation and emission, SiRNO enabled the detection of NO in situ in the xenograft tumor mouse model, revealing the NO generation during the tumor progression. This work indicates that SiR can be an ideal platform for the development of NIR emissive TP probe and may thus promote the advancement of NIR imaging.

Molecular detection of genotype II grass carp reovirus based on nucleic acid sequence-based amplification combined with enzyme-linked immunosorbent assay (NASBA-ELISA).

Grass carp reovirus (GCRV) is the causative agent of the grass carp hemorrhagic disease that has resulted in severe economic losses in the grass carp (Ctenopharyngodon idella) farming industry in China. Early diagnosis and vaccine administration are important priorities for GCRV control. In this study, a nucleic acid sequence-based amplification with enzyme-linked immunosorbent assay (NASBA-ELISA) was developed for to detect genotype II GCRV (GCRV- II). Primers specifically targeting viral RNA genome segment 6 were utilized for amplification in an isothermal digoxigenin-labeling NASBA process, resulting in DIG-labeled RNA amplicons. The amplicons were hybridized to specific biotinylated DNA probes and the products were detected colorimetrically using horseradish peroxidase and a microplate reader. The new method is able to detect GCRV at 14 copies/µL within 5h and had a diagnostic sensitivity and a specificity of 100% when GCRV-II and non-target virus were tested. This NASBA-ELISA was evaluated using a panel of clinical samples (n=103) to demonstrate that it is a rapid, effective and sensitive method for GCRV detection in grass carp aquaculture.

Expression of Sam68 Associates with Neuronal Apoptosis and Reactive Astrocytes After Spinal Cord Injury.

Src-associated in mitosis (Sam68; 68 kDa) is a novel RNA-binding protein that belongs to the signal transduction and activation of RNA family involved in various biological processes. However, the expression and roles of Sam68 in the central nervous system remain unknown. In the present study, we performed a spinal cord injury (SCI) model in adult rats and found a significant increase of Sam68 protein levels in this model, which reached a peak at day 3 and then gradually returned to normal levels at day 14 after SCI. We use immunohistochemistry analysis revealing a widespread distribution of Sam68 in the spinal cord. In addition, double-immunofluorescence staining showed that Sam68 immunoreactivity was found predominantly in neurons and astrocytes. Moreover, colocalization of Sam68/active caspase-3 has been respectively detected in neuronal nuclei, and colocalization of Sam68/PCNA has been detected in glial fibrillary acidic protein. In vitro, we found that depletion of Sam68 by short interfering RNA inhibits neuronal apoptosis and astrocyte proliferation and decreases cyclin D1 protein levels. In conclusion, this is the first study to find the Sam68 expression in SCI. Our results suggest that Sam68 might be illustrated in the apoptosis of neurons and proliferation of astrocytes after SCI. This research will provide new drug targets for clinical treatment of SCI.